Protocol for the development of guidance for stakeholder engagement in health and healthcare guideline development and implementation

Stakeholder engagement has become widely accepted as a necessary component of guideline development and implementation. While frameworks for developing guidelines express the need for those potentially affected by guideline recommendations to be involved in their development, there is a lack of consensus on how this should be done in practice. Further, there is a lack of guidance on how to equitably and meaningfully engage multiple stakeholders. We aim to develop guidance for the meaningful and equitable engagement of multiple stakeholders in guideline development and implementation. METHODS: This will be a multi-stage project. The first stage is to conduct a series of four systematic reviews. These will (1) describe existing guidance and methods for stakeholder engagement in guideline development and implementation, (2) characterize barriers and facilitators to stakeholder engagement in guideline development and implementation, (3) explore the impact of stakeholder engagement on guideline development and implementation, and (4) identify issues related to conflicts of interest when engaging multiple stakeholders in guideline development and implementation. DISCUSSION: We will collaborate with our multiple and diverse stakeholders to develop guidance for multi-stakeholder engagement in guideline development and implementation. We will use the results of the systematic reviews to develop a candidate list of draft guidance recommendations and will seek broad feedback on the draft guidance via an online survey of guideline developers and external stakeholders. An invited group of representatives from all stakeholder groups will discuss the results of the survey at a consensus meeting which will inform the development of the final guidance papers. Our overall goal is to improve the development of guidelines through meaningful and equitable multi-stakeholder engagement, and subsequently to improve health outcomes and reduce inequities in health

Restoring tumour selectivity of the bioreductive prodrug pr-104 by developing an analogue resistant to aerobic metabolism by human aldo-keto reductase 1c3

PR-104 is a phosphate ester pre-prodrug that is converted in vivo to its cognate alcohol, PR-104A, a latent alkylator which forms potent cytotoxins upon bioreduction. Hypoxia selectivity results from one-electron nitro reduction of PR-104A, in which cytochrome P450 oxidoreductase (POR) plays an important role. However, PR-104A also undergoes ‘off-target’ two-electron reduction by human aldo-keto reductase 1C3 (AKR1C3), resulting in activation in oxygenated tissues. AKR1C3 expression in human myeloid progenitor cells probably accounts for the dose-limiting myelotoxicity of PR-104 documented in clinical trials, resulting in human PR-104A plasma exposure levels 3.4- to 9.6-fold lower than can be achieved in murine models. Structure-based design to eliminate AKR1C3 activation thus represents a strategy for restoring the therapeutic window of this class of agent in humans. Here, we identified SN29176, a PR-104A analogue resistant to human AKR1C3 activation. SN29176 retains hypoxia selectivity in vitro with aerobic/hypoxic IC(50) ratios of 9 to 145, remains a substrate for POR and triggers γH2AX induction and cell cycle arrest in a comparable manner to PR-104A. SN35141, the soluble phosphate pre-prodrug of SN29176, exhibited superior hypoxic tumour log cell kill (>4.0) to PR-104 (2.5–3.7) in vivo at doses predicted to be achievable in humans. Orthologues of human AKR1C3 from mouse, rat and dog were incapable of reducing PR-104A, thus identifying an underlying cause for the discrepancy in PR-104 tolerance in pre-clinical models versus humans. In contrast, the macaque AKR1C3 gene orthologue was able to metabolise PR-104A, indicating that this species may be suitable for evaluating the toxicokinetics of PR-104 analogues for clinical development. We confirmed that SN29176 was not a substrate for AKR1C3 orthologues across all four pre-clinical species, demonstrating that this prodrug analogue class is suitable for further development. Based on these findings, a prodrug candidate was subsequently identified for clinical trials

Searching for the Majority: Algorithms of Voluntary Control

Voluntary control of information processing is crucial to allocate resources and prioritize the processes that are most important under a given situation; the algorithms underlying such control, however, are often not clear. We investigated possible algorithms of control for the performance of the majority function, in which participants searched for and identified one of two alternative categories (left or right pointing arrows) as composing the majority in each stimulus set. We manipulated the amount (set size of 1, 3, and 5) and content (ratio of left and right pointing arrows within a set) of the inputs to test competing hypotheses regarding mental operations for information processing. Using a novel measure based on computational load, we found that reaction time was best predicted by a grouping search algorithm as compared to alternative algorithms (i.e., exhaustive or self-terminating search). The grouping search algorithm involves sampling and resampling of the inputs before a decision is reached. These findings highlight the importance of investigating the implications of voluntary control via algorithms of mental operations

S100A7-Downregulation Inhibits Epidermal Growth Factor-Induced Signaling in Breast Cancer Cells and Blocks Osteoclast Formation

S100A7 is a small calcium binding protein, which has been shown to be differentially expressed in psoriatic skin lesions, as well as in squamous cell tumors of the skin, lung and breast. Although its expression has been correlated to HER+ high-grade tumors and to a high risk of progression, the molecular mechanisms of these S100A7-mediated tumorigenic effects are not well known. Here, we showed for the first time that epidermal growth factor (EGF) induces S100A7 expression in both MCF-7 and MDA-MB-468 cell lines. We also observed a decrease in EGF-directed migration in shRNA-downregulated MDA-MB-468 cell lines. Furthermore, our signaling studies revealed that EGF induced simultaneous EGF receptor phosphorylation at Tyr1173 and HER2 phosphorylation at Tyr1248 in S100A7-downregulated cell lines as compared to the vector-transfected controls. In addition, reduced phosphorylation of Src at tyrosine 416 and p-SHP2 at tyrosine 542 was observed in these downregulated cell lines. Further studies revealed that S100A7-downregulated cells had reduced angiogenesis in vivo based on matrigel plug assays. Our results also showed decreased tumor-induced osteoclastic resorption in an intra-tibial bone injection model involving SCID mice. S100A7-downregulated cells had decreased osteoclast number and size as compared to the vector controls, and this decrease was associated with variations in IL-8 expression in in vitro cell cultures. This is a novel report on the role of S100A7 in EGF-induced signaling in breast cancer cells and in osteoclast formation

Antibiotic research and development: business as usual?

This article contends that poor economic incentives are an important reason for the lack of new drugs and explains how the DRIVE-AB intends to change the landscape by harnessing the expertise, motivation and diversity of its partner

Collection Development in Canadian Academic Libraries

Music librarians with shrinking acquisitions budgets, crowded shelves, and pressure to create more student study space face fundamental questions: How do we sustain the quality of the music collection with limited funds? How can we be proactive with collection development when so much is beyond our control? Houman and Carolyn will present survey results that capture a snapshot of the current state of music acquisition funds and collection building activities in Canadian academic libraries. In particular, they will cover how these funds are organized, where they are being spent, and how fluctuations in institutional support for library collections may impact music collection-building mandates across Canada. Since the fall in the Canadian dollar and the lower purchasing power of the library, this survey may be used to develop contingency measures to examine potential changes in the area of music collection development. Jan and Kevin will review the pros and cons of two potential responses to shrinking budgets. First, seeking donations (monetary or in-kind). Endowed funds can increase acquisitions budgets, but are vulnerable to market fluctuations. They can also come with donor restrictions. In-kind donations add value to our collections but require staff resources to process and catalogue. Second, collaborating with other music librarians to highlight unique collections and avoid duplication of effort. Successful collaboration depends on like personalities, geography, and institutional support. Do music librarians in Canada have enough purchasing power to negotiate with vendors? Can librarians serving different institutions and patron communities find a coordinated future together

Alexithymic Trait and Voluntary Control in Healthy Adults

Background: Alexithymia is a personality trait characterized by deficiency in understanding, processing, or describing emotions. Recent studies have revealed that alexithymia is associated with less activation of the anterior cingulate cortex, a brain region shown to play a role in cognitive and emotional processing. However, few studies have directly investigated the cognitive domain in relation to alexithymia to examine whether alexithymic trait is related to less efficient voluntary control. Methodology / Principal Findings: We examined the relationship between alexithymic trait and voluntary control in a group of healthy volunteers. We used the 20-item Toronto Alexithymia Scale (TAS-20) to measure alexithymic trait. Additionally, we examined state and trait voluntary control using the revised Attention Network Test (ANT-R) and the Adult Temperament Questionnaire (ATQ), respectively. Alexithymic trait was positively correlated with the overall reaction time of the ANT-R, and negatively correlated with the Effortful Control factor of the ATQ

Illustration of representative stimulus configurations of the majority function task.

<p>In this task, arrows with set sizes of 1, 3, or 5 are randomly presented at 8 possible locations arranged as an octagon centered on a fixation cross. The arrows point either left or right, and are presented simultaneously. Participants' task is to indicate the direction in which the majority of arrows point. For example, if three arrows are presented, and two point to the left and one to the right (see the “2∶1” panel in the “Set size 3” column), the correct response should be “left”. The eight circles are for illustration of the locations and are not displayed during the experiment. The label for each condition is the ratio of the numbers in each category.</p